Rivaroxaban for the prevention of venous thromboembolism following major orthopedic surgery: the RECORD trials

Patients undergoing total hip or knee arthroplasty face an increased risk for venous thromboembolism in the days and weeks following surgery. Hence, the routine application of prophylactic strategies is currently recommended. These include parenteral anticoagulants such as the low-molecular-weight heparins or fondaparinux and oral anticoagulants such as warfarin. New anticoagulant drugs are rapidly becoming available, including drugs that are administered orally, at fixed doses and without laboratory monitoring. Rivaroxaban is the first of a new class of anticoagulants: the selective, direct Factor Xa inhibitors. It has completed clinical evaluation in the setting of major orthopedic surgery and is now approved in many countries for the prevention of venous thromboembolism in patients undergoing total knee and hip arthroplasty. In this paper, we will review the trial data now supporting the clinical use of rivaroxaban and will discuss the potential role of this agent in daily clinical practice.     

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery – TREK: a dose-ranging study

Summary.  Background: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. Objectives: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. Patients/methods: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. Results: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention ( P  <   0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT ( P  =   0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding ( P  =   0.0231) and any bleeding ( P  =   0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. Conclusions: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.     

Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART Study

Summary.  Background:  In Asian patients undergoing surgery, the incidence of venous thromboembolism (VTE) is thought to be low relative to Western patients, and the routine use of thromboprophylaxis is controversial. Objectives:  The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. Patients and methods:  We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary study outcome was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month's follow-up. Results:  Between April 2001 and July 2002, 2420 patients were enrolled. Median age was 68 years and the median duration of hospital stay was 13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3%[55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI 0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors ( P <  0.05) for the occurrence of the primary endpoint. At 1 month's follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients). Conclusion:  In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in Western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures.     

Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO‐TEP registry

Summary. Background: Thromboprophylaxis with rivaroxaban (R) is superior to enoxaparin in patients undergoing major orthopedic surgery (MOS). However, rivaroxaban has never been directly compared with fondaparinux (F), which also shows superior efficacy over enoxaparin. The clinical impact of switching from fondaparinux to rivaroxaban thromboprophylaxis is unclear. Objectives: To evaluate the efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in unselected patients undergoing MOS. Patients/Methods: This is a monocentric, retrospective cohort study in 5061 consecutive patients undergoing MOS at our centre, comparing rates of symptomatic VTE, bleeding and surgical complications, length of hospital stay and risk factors for VTE. Results: Rates of symptomatic VTE were 5.6% (F) and 2.1% (R; P < 0.001), with rates for distal DVT being 3.9 vs. 1.1% (P < 0.001). Rates of major VTE were numerically higher with fondaparinux (1.8 vs. 1.1%), but not statistically significant. Rates of severe bleeding (bleeding leading to surgical revision or death, occurring in a critical site, or transfusion of at least two units of packed red blood cells) were statistically lower with rivaroxaban compared with fondaparinux (2.9 vs. 4.9%; P = 0.010). The mean length of hospital stay was significantly shorter in the rivaroxaban group (8.3 days, 95% CI 8.1–8.5 vs. 9.3 days, 9.1–9.5; P < 0.001). Conclusion: Based on an indirect comparison of two consecutive cohorts, our data suggest that thromboprophylaxis with rivaroxaban is associated with less VTE and bleeding events than fondaparinux in unselected patients undergoing MOS. Prospective comparisons are warranted to confirm our findings.     

骨科大手术术后发生静脉血栓栓塞的影响因素分析

目的探讨骨科大手术术后发生静脉血栓栓塞(VTE)的影响因素。方法选取2017年2月至2019年2月在我院进行骨科大手术的患者120例为研究对象,术后4个月内发生VTE患者53例,采用多因素logistic回归分析发生VTE的高危因素。结果多因素logistic回归分析显示,肥胖、高血压病、糖尿病、血栓史、纤维蛋白原(FIB)、同型半胱氨酸(Hcy)、手术时间、手术体位是影响骨科大手术术后患者发生VTE的独立危险因素(P<0.05)。结论骨科大手术术后发生VTE是由多种危险因素共同导致的,医护人员进行术后护理需要掌握患者基本情况,针对性实施预防措施,降低发生VTE的风险。     

Single intravenous administration of TB‐402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose‐escalating,randomized, controlled trial

Summary. Background: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg^?1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg^?1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg^?1.     

The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery

Summary.  Background : The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. Objectives : To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. Patients/methods : A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. Results : In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are £27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. Results are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. Conclusions : Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.     

Incidence, risk profile and morphological pattern of venous thromboembolism after prostate cancer surgery

Summary.  Background : Venous thromboembolism (VTE) is the most common non-surgical complication after major pelvic surgery. Little is known about the risk factors or the time of development of postoperative venous thrombosis. Methods: A cohort of 523 consecutive patients undergoing radical prostatectomy with lymphadenectomy was prospectively assessed by complete compression ultrasound at days −1, +8 and +21. Results: Complete data were available in 415 patients, while four patients had VTE before surgery and were excluded from the analysis. In the remaining 411 patients, 71 VTE events were found in 69 patients (16.8%). Most were limited to calf muscle veins (56.5%), followed by deep calf vein thrombosis (23.2%), proximal deep vein thrombosis (DVT, 14.5%) and pulmonary embolism (PE, 5.8%). Of the 14 patients with proximal DVT/PE, 11 patients (78.6%) developed VTE between days 8 and 21. Risk factors for VTE were a personal history of VTE (OR 3.0), pelvic lymphoceles (LCs) impairing venous flow (OR 2.8) and necessity of more than two units of red blood cells (OR 2.6). Conclusion: Venous thromboembolism is common after radical prostatectomy. A significant proportion develops after day 8, suggesting that prolonged heparin prophylaxis should be considered. Since LCs with venous flow reduction result in higher rates of VTE, hemodynamically relevant lymphoceles should be surgically treated.     

Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement

BACKGROUND: Joint replacement surgery is an appropriate model for dose-ranging studies investigating new anticoagulants. OBJECTIVES: To assess the efficacy and safety of a novel, oral, direct factor Xa (FXa) inhibitor--BAY 59-7939--relative to enoxaparin in patients undergoing elective total hip replacement. METHODS: In this double-blind, double-dummy, dose-ranging study, patients were randomized to oral BAY 59-7939 (2.5, 5, 10, 20, or 30 mg b.i.d.), starting 6-8 h after surgery, or s.c. enoxaparin 40 mg once daily, starting on the evening before surgery. Treatment was continued until mandatory bilateral venography was performed 5-9 days after surgery. RESULTS: Of 706 patients treated, 548 were eligible for the primary efficacy analysis. The primary efficacy endpoint was the incidence of any deep vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality; rates were 15%, 14%, 12%, 18%, and 7% for BAY 59-7939 2.5, 5, 10, 20, and 30 mg b.i.d., respectively, compared with 17% for enoxaparin. The primary efficacy analysis did not demonstrate any significant trend in dose-response relationship for BAY 59-7939. The primary safety endpoint was major, postoperative bleeding; there was a significant increase in the frequency of events with increasing doses of BAY 59-7939 (P = 0.045), but no significant differences between individual BAY 59-7939 doses and enoxaparin. CONCLUSIONS: When efficacy and safety were considered together, the oral, direct FXa inhibitor BAY 59-7939, at 2.5-10 mg b.i.d., compared favorably with enoxaparin for the prevention of venous thromboembolism in patients undergoing elective total hip replacement.     

Effect of age on the incidence of venous thromboembolism after major surgery

BACKGROUND: Most guidelines for administration of thromboprophylaxis after major surgery use age as a major predictor of postoperative venous thromboembolism (VTE). We sought to quantify the effect of age on the risk of symptomatic VTE after a spectrum of surgical procedures. METHODS: Using the California Patient Discharge Data Set and specific ICD-9-CM surgical procedure codes, we retrospectively determined the incidence of VTE diagnosed within 91 days after 40 different urgent or elective surgeries performed in the hospital between 1992 and 1996. Logistic regression was used to quantify the effect of age on the incidence of postoperative VTE and to adjust for other risk factors. RESULTS: 1,464,452 cases underwent one of 40 different procedures (mean cases per procedure = 35,718, range 4500-145 500). There was a significant interaction between age and the type of surgery performed (P<0.0001). Qualitative analysis of the effect of age on the incidence of VTE stratified by the presence or absence of malignancy revealed three general patterns: a steady increase in the incidence of VTE with age, exemplified by appendectomy or cholecystectomy; an increase in VTE up to approximately age 65 with no increase thereafter, exemplified by total hip arthroplasty; and no effect of age on the incidence of VTE, exemplified by vascular surgery. CONCLUSIONS: The relationship between age and the risk of VTE after surgery is complex and depends on the nature of the surgery and the underlying pathologic process. Advancing age was a significant predictor for VTE following surgeries performed for conditions not inherently associated with significant comorbidity. Conversely, advancing age was not associated with a higher incidence of VTE after surgeries performed for conditions strongly associated with serious underlying comorbidity, such as a malignancy or severe peripheral vascular disease.     

Incidence of venous thromboembolism following major abdominal surgery: a multi-center, prospective epidemiological study in Japan

BACKGROUND: Venous thromboembolism (VTE) has been considered to be a rare surgical complication in Japan. AIM: To investigate the incidence and risk factors of VTE in Japanese patients undergoing major abdominal surgery. METHODS: A prospective, multi-center epidemiological study was conducted from December, 2001 to August 2002 in 39 medical institutes throughout Japan. A total of 173 patients with general (n = 128), gynecologic (n = 23), and urologic (n = 22) surgery were analyzed. For the diagnosis of deep vein thrombosis (DVT), bilateral venography was performed in all patients. Lung ventilation/perfusion scintigraphy was carried out in patients suspected of pulmonary thromboembolism (PTE). RESULTS: There were 36 patients with distal DVT (20.8%) and five patients with proximal DVT (2.9%). One patient was diagnosed as PTE. Overall, VTE was diagnosed in 42 patients (24.3%). By univariate analysis, only age (60 years or older) was identified as a significant risk factor in the whole study population. When analyzed by the stepwise multiple logistic regression model, female gender, operation site, age, and operation time were four risk factors found to be significant. The incidence of VTE was closely related to the number of risk factors that patients had. As many as 44% of patients with three or four risk factors developed VTE while those with one or two risk factors showed about a 17% incidence of VTE. Four patients lacking any risk factors did not develop VTE. CONCLUSIONS: Venous thromboembolism is common in Japanese patients undergoing major abdominal surgery. Pharmacologic thromboprophylaxis is considered essential, particularly in those patients with multiple, potential risk factors.     

Efficacy and safety of bemiparin compared with enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind clinical trial

Summary.  In this randomized, multicenter, controlled, double-blind, sequential trial, 381 patients undergoing primary total knee replacement were randomly assigned to receive subcutaneous injections of either 3500 IU anti-factor Xa of bemiparin sodium, first dose 6 h after surgery, or 40 mg of enoxaparin, first dose 12 h before surgery, followed by daily doses for 10 ± 2 days, for the prophylaxis of venous thromboembolism. The primary efficacy endpoint was venous thromboembolism up to postoperative day 10 ± 2, defined as deep vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep vein thrombosis and/or documented symptomatic pulmonary embolism. The primary safety endpoint was major bleeding. Eighty-seven percent of all randomized patients (333 of 381 patients) were evaluable for efficacy. The incidence of venous thromboembolism was 32.1% (53 of 165 patients) in the bemiparin group and 36.9% (62 of 168 patients) in the enoxaparin group. The absolute risk difference was 4.8% in favor of bemiparin [95% confidence interval (CI), −15.1% to 5.6%; non-inferiority P -value: 0.02; superiority P -value: 0.36]. The incidence of proximal deep vein thrombosis was 1.8% (three of 165 patients) in the bemiparin group and 4.2% (seven of 168 patients) in the enoxaparin group. Major bleeding occurred in six patients (three in each group). There were no deaths during the study. This trial shows that bemiparin started postoperatively is as effective and safe as enoxaparin started preoperatively in the prevention of venous thromboembolism in patients undergoing total knee replacement.     

Recurrent venous thromboembolism after surgery‐provoked versus unprovoked thromboembolism

Summary. Background: The incidence of recurrent venous thromboembolism (VTE) varies depending on the nature of the initial provoking risk factor(s). Objectives: To compare the incidence and time course of recurrent VTE after unprovoked VTE vs. VTE provoked by nine different types of surgery. Methods: Retrospective analysis of linked California hospital and emergency department discharge records. Between 1997 and 2007, all surgery‐provoked VTE cases had a first‐time VTE event diagnosed within 60 days after undergoing a major operation. The incidence of recurrent VTE was compared during specified follow‐up periods by matching each surgery‐provoked case with three unprovoked cases based on age, race, gender, VTE event, calendar year and co‐morbidity. Results: The 4‐year Kaplan–Meier cumulative incidence of recurrent VTE was 14.7% (95%CI: 14.2–15.1) in the matched unprovoked VTE group vs. 7.6% (CI: 7.0–8.2) in 11 797 patients with surgery‐provoked VTE (P < 0.001). The overall risk reduction was 48%, which ranged from 64% lower risk (P < 0.001) after coronary bypass surgery to 25% lower risk (P = 0.06) after disc surgery. The risk of recurrent VTE 1–5 years after the index event was significantly lower in the surgery group (HR = 0.47, CI: 0.41–0.53). Within the surgery‐provoked group, the risk of recurrent VTE was similar in men and women (HR = 1.0, CI: 0.8–1.3). Conclusions: The risk of recurrent VTE after surgery‐provoked VTE was approximately 50% lower than after unprovoked VTE, confirming the view that provoked VTE is associated with a lower risk of recurrent VTE. However, there was appreciable heterogeneity in the relative risk of recurrent VTE associated with different operations.     

BAY 59-7939: an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study

BACKGROUND: BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. METHODS: In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. RESULTS: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939. CONCLUSIONS: Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.